Alt. symbols: MST1 | KRS2 | YSK3

Approved name: serine/threonine kinase 4
Alt. names: mammalian sterile 20-like 1, yeast Ste20-like, kinase responsive to stress 2, hippo (Drosophila) homolog

Location: 20q13.12: 44966494 - 45084214 (+)
Gene type: protein_coding, 17 transcripts.

Scores: LoFtool: 0.526000 | pLI: 0.11831192 | LOEUF: 0.524

HGNC: 11408

NCBI: 6789, RefSeq: NG_032172.1

Ensembl: ENSG00000101109.14

LRG_535 | Status: public

OMIM: 604965

Expression | ProteinAtlas

This gene encodes the STK4/MST1 protein, which is the human ortholog of Drosophila Hippo, belonging to a group of conserved and ubiquitously expressed serine/threonine kinases regulating cell proliferation and survival through the Hippo pathway. More recent evidence has also implicated STK3/4 in the regulation of various different cellular processes, including activation of immune responses, through the non-canonical Hippo pathway. The Hippo signaling pathway plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. In keeping with its roles in regulating cell growth, proliferation, and differentiation, STK4 has been noted to be a tumor suppressor that regulates cell differentiation and apoptosis in breast cancer and hepatocellular carcinoma (PMID: 29954663). STK4 regulates innate and adaptive immunity via the non-canonical Hippo pathway. In T lymphocytes, STK4 promotes T cell adhesion, migration, and homing downstream of G protein-coupled receptors and the T cell receptor (TCR) (PMID: 22711877) and regulates the balance between Tregs and Th17 cells through inhibition of signaling pathways downstream of TGF-? and IL-6/IL-23, favoring FoxP3+ Treg development and inhibition of ROR?t dependent Th17 cell responses (PMID: 26538561). STK4 is also involved in neutrophil extravasation through STK4-dependent Rab27a trafficking vesicles containing integrins (PMID: 26801501). In macrophages, STK4 has been assigned a role in Toll-like receptor (TLR)/MyD88-dependent generation of mitochondrial reactive oxygen species, thus enhancing phagosomal degradation of endocytosed microbial pathogens (PMID: 20865019). A recent study linked the Hippo and non-canonical Hippo pathways, thus connecting cellular nutrient/physical status with host antiviral defense, by demonstrating that YAP/TAZ proteins of the Hippo pathway act as natural inhibitors of TBK1, a central kinase in nucleic acid sensing and IFN production (PMID: 28346439).

Biallelic nonsense and frameshift mutations in STK4 lead to an autosomal recessive syndrome featuring T cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations [OMIM:614868]. Patients often present with recurrent bacterial, viral, and fungal infections, including pneumonia, skin abscesses, cutaneous HPV-induced warts, and chronic mucocutaneous candidiasis, as well as autoimmune cytopenias (PMID: 22294732, 22952854, 22174160, 26801501, 30386345, 33078349). Immunopheno typing may find reduced naïve T cell levels, impaired T cell responses, reduced T cell proliferation, and increased T cell apoptosis. STK4 deficient patients characteristically display hypergammaglobulinemia despite inadequate vaccine responses and some may produce auto-antibodies against thyroglobulin, rheumatoid factor, and proteinase 3. Continuous or intermittent neutropenia in the setting of normal bone marrow analysis has also been reported, suggesting neutrophil loss to be immune-mediated or due to increased apoptosis. Jorgenson et al. (2020) recently reported that patient cells also show significantly reduced interferon (IFN) responses to PAMPs, viruses, and bacteria due to impaired TBK1 and IRF3 phosphorylation, as well as disturbed autophagy pathways with evidence of enhanced autophagy at the single cell level (PMID: 33078349). The STK4 protein consists of an N-terminal kinase domain, a coiled coil domain, two caspase 3 cleavage sites, and a C-terminal SARAH domain responsible for ligand binding. Most of the mutations identified to date in patients have been localized within the kinase domain, though one is a deletion in the caspase 3 cleavage domain and one is located at the 5? end of the kinase domain (PMID: 33078349). [Load More]